A non-coding variant in the 5' UTR of DLG3 attenuates protein translation to cause non-syndromic intellectual disability

作者：Kumar Raman; Ha Thuong; Pham Duyen; Shaw Marie; Mangelsdorf Marie; Friend Kathryn L; Hobson Lynne; Turner Gillian; Boyle Jackie; Field Michael; Hackett Anna; Corbett Mark; Gecz Jozef^*

来源：European Journal of Human Genetics, 2016, 24(11): 1612-1616.

DOI：10.1038/ejhg.2016.46

Intellectual disability (ID) is a clinically complex and heterogeneous disorder, which has variable severity and may be associated with additional dysmorphic, metabolic, neuromuscular or psychiatric features. Although many coding variants have been implicated in ID, identification of pathogenic non-coding regulatory variants has only been achieved in a few cases to date. We identified a duplication of a guanine on chromosome X, NC_000023.10:g.69665044dupG 7 nucleotides upstream of the translational start site in the 5' untranslated region (UTR) of the known ID gene DLG3 that encodes synapse-associated protein 102 (SAP102). The dupG variant segregated with affected status in a large multigenerational family with non-syndromic X-linked ID and was predicted to disrupt folding of the mRNA. When tested on blood cells from the affected individuals, DLG3 mRNA levels were not altered, however, DLG3/SAP102 protein levels were. We also showed by dual luciferase reporter assay that the dupG variant interfered with translation. All currently known pathogenic DLG3 variants are predicted to be null, however the dupG variant likely leads to only a modest reduction of SAP102 levels accounting for the milder phenotype seen in this family.

• 出版日期2016-11